CN103269691A - Oral pharmaceutical tablet for controled release of mesalazine and process for obtaining it - Google Patents

Oral pharmaceutical tablet for controled release of mesalazine and process for obtaining it Download PDF

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Publication number
CN103269691A
CN103269691A CN2011800629130A CN201180062913A CN103269691A CN 103269691 A CN103269691 A CN 103269691A CN 2011800629130 A CN2011800629130 A CN 2011800629130A CN 201180062913 A CN201180062913 A CN 201180062913A CN 103269691 A CN103269691 A CN 103269691A
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weight
tablet
amount
oral drugs
mesalazine
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D·罗彻斯布拉斯
R·巴拉斯费尔南德斯-莫里纳
M·马丁内斯佩雷斯
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Laboratorios Liconsa SA
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/192Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/60Salicylic acid; Derivatives thereof
    • A61K31/606Salicylic acid; Derivatives thereof having amino groups
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806Coating materials
    • A61K9/2833Organic macromolecular compounds
    • A61K9/284Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846Poly(meth)acrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Abstract

The invention provides an oral pharmaceutical tablet for controlled release of mesalazine or a pharmaceutically acceptable salt thereof as active ingredient with a core and a gastro-resistant outer coating, wherein the core comprises mesalazine and a hydrophilic matrix consisting of a mixture of hydroxypropylmethyl cellulose (HPMC) having a different viscosity and the gastro-resistant outer coating comprises a pH- dependent release polymer, with the pharmaceutically acceptable excipients. The invention also refers to the process for obtaining said oral pharmaceutical tablet and to said oral pharmaceutical tablet of controlled release of mesalazine for treating ulcerative colitis.

Description

Be used for oral drugs tablet and its preparation method that control discharges mesalazine
Technical field
The present invention relates to control release as the mesalazine (mesalazine) of the active component oral drugs tablet of---being also referred to as U.S. salad bright (mesalamine) or 5-aminosalicylic acid---.
The invention still further relates to the method for the described oral drugs tablet of acquisition and the oral drugs control release tablet of described mesalazine and be used for the treatment of ulcerative colitis.
Background technology
Inflammatory bowel (IBD) is a series of chronic idiopathic inflammatory bowel.IDB causes significant GI symptom, comprises diarrhoea, stomachache, hemorrhage, anemia and loses weight.IBD is also relevant with the outer performance form of a series of intestinal, comprises arthritis, ankylosing spondylitis, sclerosing cholangitis, uveitis, iritis, PG and erythema nodosum.
IBD is divided into two kinds of main subclass: ulcerative colitis and Crohn disease (Chron ' s disease).Ulcerative colitis be characterized as the colon amalgamation mucosal inflammation that begins at anal verge, and to extend (for example proctitis, left side colitis or pancolitis) to neighbouring (proximally) in various degree.By contrast, the saturating wall inflammation at any position that is characterized as the GI road of Crohn disease, but modal position is the zone of contiguous ileocecal valve.
Generally include mesalazine (5-aminosalicylic acid or 5-ASA) to slightly treating to first line of moderate ulcerative colitis.Mesalazine is the aminosallcylic acid (5-aminosalicylic acid) with antiinflammatory property.Shown that mesalazine can be used for inducing active stage slightly to the alleviation of moderate patients of ulcerative colitis.Its chemical name is the 5-amino-2-hydroxybenzoic acid, and its structural formula is:
Figure BDA00003413721700011
When per os gave mesalazine, high amount of drug was absorbed in upper gastrointestinal, caused systemic side effects.The mechanism of action of mesalazine imperfectly understands, but seemingly local.
Therefore, the specific delivery that needs medicine described in the colon with mesalazine treatment ulcerative colitis.This specific delivery has improved effectiveness and can reduce minimum effective dose.Having developed multiple system sends for the colon-specific medicine.Because the pH difference between small intestinal and the colon, the enteric coating system is most commonly used to colonic drug delivery.
Have several slow release mesalazine preparations, its present commercialization is used for the treatment of slight UC acute exacerbation to moderate and keeps alleviation.
Develop effective mesalazine slow releasing composition and hindered by such fact, namely when comparing with the immediate release composition with identical activity, the compositions of the type contains the active component of higher concentration usually.Another problem that conventional sustained release forms frequently runs into is the time of staying that can not be increased in absorption window.
Patent application WO 03/011205-A discloses the controlled release capsule sheet of nifedipine, it comprises, and (viscosity is respectively 13 by HPMC K15M and HPMC K100M, 275-24,780mPas and 75,000-140, the substrate that 1: 1 mixture 000mPas) is formed, (seeing Table 1) its administration that discharges from the zero level with active component begins to provide the release of active component.After its administration 5 hours, discharged 50% active component.After its administration 10 hours, active component discharges from described preparation fully.
Patent application WO 00/76481-A discloses and has contained mesalazine as the control release tablet of active component, it comprises inside lipotropy substrate Brazil wax and the outer hydrophilic matrix hydroxypropyl emthylcellulose for example for example that fusing point is lower than 90 ℃, wherein said active component be enclosed in spherical in (inglobated).Then the tablet that forms is carried out film coating so that the colonic delivery of active component to be provided with polymethacrylates.
WO 00/76481-A discloses the preparation of tablet, its by with lipophilic substance with described active component melt pelletization to obtain granule, then described granule is mixed with the hydrophilic excipient as hydrophilic matrix, then tabletting or compression.Tablet with gained carries out film coating so that the colonic delivery of active component to be provided with polymethacrylates then.
But, produced different results with the HPMC blending with the low melting point lipophilic materials that realizes control or lasting release of active ingredients.In these systems some demonstrated the prolongation that medicine can not be provided and discharged, especially when with high concentration (〉=10%w/w) during the described lipophilic materials of use.In addition, melt pelletization technology costliness, time-consuming and needs use particular device.Described melt pelletization method partially or even wholly is made up of following: make the fusion of described lipid excipient, then with active component and other mixed with excipients, by refrigeration or freezing described mixture is become granule.In the method, described active component is heated, if therefore do not control temperature carefully, described active component may partly decompose.In addition, cooling subsequently can come induced transformation by the solid-state fusion mechanism of unwanted variation in the active component release that maybe can cause.
The invention provides selectable oral drugs tablet, it has avoided the shortcoming of above-mentioned preparation.
Summary of the invention
The inventor has been found that can be by providing the strong release characteristic of matrix system need to obtain in conjunction with other HPMC of different viscosities level.
In surprise, have been found that by the hydroxypropyl emthylcellulose (HPMC) that is lower than 200mPas in 2% aqueous solution medium viscosity and be the hydrophilic matrix that 10: 1 to 1: 10 mixture is formed in the weight ratio that 2% aqueous solution medium viscosity is higher than the hydroxypropyl emthylcellulose (HPMC) of 200mPas, overcome the shortcoming of prior art preparation.
Advantageously, use control release as the new oral medicinal tablet of the mesalazine of active component, avoided the initial unexpected release of active component from substrate, and realized the required colon release profiles as the mesalazine of active component.
The present invention also provides a kind of method for preparing described oral drugs tablet, and described tablet design is used for continuing or controls release tablet as the mesalazine of active component.
At least another purpose of the present invention relates to described oral drugs tablet and is used for the treatment of ulcerative colitis.
Description of drawings
Fig. 1 shows, and is covering label with outer cover layer with before obtaining tablet of the present invention, the different stripping curves that the label that discharges with mesalazine control obtains.Symbol ■ shows the stripping curve of the label that contains 1g mesalazine and 1 weight % hydrophilic matrix (in the gross weight of described tablet), and described hydrophilic matrix is formed (embodiment 2) by the hydroxypropyl emthylcellulose (HPMC) that is lower than 200mPas in 2% aqueous solution medium viscosity and the hydroxypropyl emthylcellulose (HPMC) that is higher than 200mPas in 2% aqueous solution medium viscosity.Symbol ◆ show the stripping curve of the label that contains 1g mesalazine and 4.5 weight % hydrophilic matrixs (in the gross weight of described tablet), described hydrophilic matrix is formed (embodiment 1) by the hydroxypropyl emthylcellulose (HPMC) that is lower than 200mPas in 2% aqueous solution medium viscosity and the hydroxypropyl emthylcellulose (HPMC) that is higher than 200mPas in 2% aqueous solution medium viscosity.Symbol ▲ show the stripping curve of the label that contains 1g mesalazine and 20 weight % hydrophilic matrixs (in the gross weight of described tablet), described hydrophilic matrix is formed (embodiment 3) by the hydroxypropyl emthylcellulose (HPMC) that is lower than 200mPas in 2% aqueous solution medium viscosity and the hydroxypropyl emthylcellulose (HPMC) that is higher than 200mPas in 2% aqueous solution medium viscosity.
Fig. 2 shows the different stripping curves that discharge the oral drugs tablet acquisition of mesalazine with control of the present invention, and described tablet comprises the label of Fig. 1.Identical among the implication of symbol and Fig. 1.
Can observe from two figure, label has kept identical mesalazine stripping curve with tablet.In addition, Fig. 1 has proved that the hydrophilic matrix that uses has produced the result of extraction with needed mesalazine control release profiles in the label of tablet of the present invention.
The specific embodiment
The invention provides control and discharge as the mesalazine of active component or the oral drugs tablet of its officinal salt, wherein said tablet comprises label and the outer coating of enteric.
" control discharge mesalazine " used herein means, and compares with quick releasing formulation, and being released in a period of time of mesalazine is the dosage form of (or the continuing) of slowing down in the dosage form.
According to the present invention, mesalazine can be any crystallization or amorphous form.
Therefore, the invention provides control and discharge as the mesalazine of active component or the oral drugs tablet of its officinal salt, it has label and the outer coating of enteric, it is characterized in that
Described label comprises:
I) in described tablet total weight amount, 40-90 weight %, preferred 50-90 weight %, the more preferably mesalazine of 60-80 weight %; With
Ii) in the gross weight of described tablet, amount is 1-20 weight %, preferred 1-15 weight %, more preferably 2-10 weight %, still the more preferably hydrophilic matrix of 3-5 weight %, described hydrophilic matrix by the hydroxypropyl emthylcellulose (HPMC) that is lower than 200mPas in 2% aqueous solution medium viscosity and the hydroxypropyl emthylcellulose (HPMC) that is higher than 200mPas in 2% aqueous solution medium viscosity with 10: 1-1: 10 weight ratio, preferred 1: 1 weight ratio are formed;
The outer coating of described enteric comprises:
Iii) amount is the pH dependent release polymer of the outer tectal 15-75 weight % of described tablet, and wherein in the gross weight of described tablet, the tectal amount of described skin is 5-25%, preferred 10-20%.
In surprise, the HPMC polymer with two kinds of viscosity grades of these ratios provides the hydrophilic matrix of the physical property with improvement, and it shows similar stripping curve under different mixing speeds.
The HPMC polymer that is fit to comprises with trade mark
Figure BDA00003413721700041
(Dow Chemical Corporation) or
Figure BDA00003413721700042
(Shin-Etsu) those of Xiao Shouing.Polymer chemistry and the viscosity of the different families of MethocelHPMC see table 1.Number designation behind each letter is illustrated in 25 ℃ of following 2wt% viscosity in aqueous solution.
Table 1
Figure BDA00003413721700051
In a preferred embodiment, described hydrophilic matrix is to be that 2% aqueous solution (Methocel K100 Premium LV) and the viscosity of 80-120mPas is the 2% aqueous solution (METHOCEL of 2663-4970mPas by viscosity TMK4M Premium) weight ratio is that 1: 1 mixture is formed.
The tablet of described preparation can be with one or more layers pH dependent release polymer overmold.
Term used herein " pH dependent release polymer " is also referred to as enteric polymer, refer under the peracidity pH under one's belt soluble, but under low acid (relatively alkalescence) pH dissolved polymers rapidly.According to the present invention, described pH dependent release polymer can not dissolve in the acidic liquid (pH~3) of stomach, but is that small intestinal 5.5 or more or pH understand under the higher pH environment that exists in the colon 7.0 or more to dissolve at pH.
Select pH dependent release polymer, make mesalazine when described dosage form arrives entrance between small intestinal and the colon, or in colon, be released thereafter.Described selection is based on the pH curve of small intestinal and colon.The about 5-5.5 of the pH of small intestinal from pyloric cap is increased to about 7.2 in the small intestinal extremity (ileum) gradually.Described pH significantly drops to about 6.3 at ileocecus, and little by little increases to about 7 in left side colon or the descending colon.
The inventor finds that other HPMC of use high viscosity grade makes described label expand as matrix forming agent (former) and degrades gradually in the time in a few hours, because it has increased gel strength after absorbing gastric juice.The HPMC that adds lower viscosity levels has avoided the initial suddenly release of active component from substrate, therefore it is degraded constantly.Describedly degrade process and surface in described dosage form contact the back with gastric juice just initial with the expansion process while.Degrade and reflect the stripping of described polymer after gel-solution interface forms, the described polymer of described gel-solution interface become enough dilutions so that described active component can from described dosage form, transport by diffusion or convection current.
Hydrophilic matrix of the present invention provides required colon release profiles, and this provides the lasting release of active component in required absorption window.
Use oral drugs tablet of the present invention to realize the release of mesalazine in colon, for described colon, pharmacologically active needed in the time from the remarkable delay of oral administration time.Consider the path of tablet from its oral administration to colon, oral drugs tablet of the present invention provides enough colon release profiles.
Preferred pH dependent release polymer is, is kept perfectly in the low pH environment of harmonization of the stomach small intestinal, but is more than 6.3 at pH, and preferred pH is those polymer that begin to dissolve in the aqueous solution of 6.8-7.2.Preferred enteric polymer is selected from poly-(methacrylic acid, methyl methacrylate) 1: 2
Figure BDA00003413721700061
And gathered (methacrylic acid, methyl methacrylate) 1: 1
Figure BDA00003413721700062
With poly-(methacrylic acid, methyl methacrylate) 1: 2
Figure BDA00003413721700064
Ratio be about 1: 10 to about 1: 1, preferred about 1: 5 to about 1: 3 mixture.Especially be preferably With Or its mixture.Especially be preferably
Figure BDA00003413721700067
With
Figure BDA00003413721700068
1: 10 to 10: 1 mixture.
In a preferred embodiment, the amount of described pH dependent release polymer is the outer tectal 15-75 weight % of described tablet.
Preferably, in the gross weight of described tablet formulation, outer cover layer amount is 5-25%, preferred 10-20%.
Randomly, described label also comprises filler, binding agent, antitack agent, lubricant and disintegrating agent as pharmaceutically acceptable excipient.Randomly, the outer cover layer of described tablet also comprises antitack agent, plasticizer and coloring agent as pharmaceutically acceptable excipient.
Preferably, tablet of the present invention comprises filler.The material that is commonly used for filler includes but not limited to glucose, lactose, lactose monohydrate, fructose, mannitol, microcrystalline Cellulose, starch, pregelatinized starch, powdery cellulose, silication cellulose, Sorbitol, sucrose and Talcum, or its mixture.Preferred filler is microcrystalline Cellulose.The amount of described filler can be the 0.5-10 weight % of described tablet total weight amount, preferred 0.5-8 weight %, more preferably 1-5 weight %.
Preferably, tablet of the present invention comprises binding agent (binding agent or binder).The material that is commonly used for binding agent includes but not limited to polyvinylpyrrolidone, hyprolose, hydroxypropyl emthylcellulose, hydroxyethyl-cellulose, methylcellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, carboxymethylcellulose calcium and/or its mixture.Preferred adhesive is polyvinylpyrrolidone.The amount of described binding agent can be the 0.1-10 weight % of described tablet total weight amount, preferred 0.5-9 weight %, more preferably 1-7.5 weight %.
Preferably, tablet formulation of the present invention comprises antitack agent in label.Described outer cover layer also can comprise antitack agent to eliminate the adhesion in the film coating process.
The material that is commonly used for antitack agent includes but not limited to colloidal silica and Talcum, preferred colloidal silica (aerosil) when being used for label, preferably talc when being used for outer cover layer.
In, the amount of described antitack agent in label is the 0.1-5 weight % of described tablet total weight amount, preferred 0.1-3.5 weight %, more preferably 0.1-1.5 weight %, and be up to 30 weight % of described outer cover layer gross weight, be preferably 5-30 weight %.
Preferably, tablet formulation of the present invention randomly comprises lubricant.The material that is commonly used for lubricant includes but not limited to for example magnesium stearate of stearic acid and stearate.Preferred lubricant is magnesium stearate.In the gross weight of described tablet, the amount of described lubricant can be 0.1-5 weight %, preferred 0.1-3 weight %.
Preferably, tablet formulation of the present invention randomly comprises disintegrating agent.The material that is commonly used for disintegrating agent includes but not limited to starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, crospovidone, cross-linked carboxymethyl cellulose sodium and/or its mixture.Preferably, described disintegrating agent is pregelatinized starch.
In the gross weight of described tablet, the amount of described disintegrating agent in described tablet label is 1-10 weight %, preferred 1-8 weight %, more preferably 2.5-7.5 weight %.
Preferably, described outer cover layer randomly comprises plasticizer so that uniform film mixture to be provided.Preferred plasticizer comprises triethyl citrate, Polyethylene Glycol or dibutyl sebacate, the optimization citric acid triethyl.In the tectal gross weight of described skin, the amount of described plasticizer can be up to 20%, preferred 5-20 weight %.
Tablet of the present invention comprises one or more pharmaceutically acceptable excipient.All these excipient must be " pharmaceutically useful ", and meaning is compatible with other compositions of described pharmaceutical composition and can be unharmful to the patient.Pharmaceutically acceptable excipient can comprise for example for example mannitol, antiseptic, stabilizing agent, antioxidant and any other excipient well known by persons skilled in the art of methanol, sweeting agent of pigment, flavoring agent.
In a preferred embodiment, medicinal tablet of the present invention comprises label and outer cover layer, described label comprises the mesalazine of 40-90 weight %, the hydroxypropyl methylcellulose mixtures of 1-20% (by the hydroxypropyl emthylcellulose (HPMC) that is lower than 200mPas in 2% aqueous solution medium viscosity and the hydroxypropyl emthylcellulose (HPMC) that is higher than 200mPas in the aqueous solution medium viscosity of 2%w/w with 1: 10-10: 1 weight ratio is formed), the microcrystalline Cellulose of 0.5-10%, 0.1-10 the pregelatinized starch of the polyvinylpyrrolidone of weight % and 1-10 weight %, described outer cover layer comprise pH dependent release polymer and one or more pharmaceutically acceptable excipient.
In a preferred embodiment, medicinal tablet of the present invention comprises label and outer cover layer, described label comprises the mesalazine of 50-90 weight %, the hydroxypropyl methylcellulose mixtures of 2-10% (by the hydroxypropyl emthylcellulose (HPMC) that is lower than 200mPas in 2% aqueous solution medium viscosity and the hydroxypropyl emthylcellulose (HPMC) that is higher than 200mPas in the aqueous solution medium viscosity of 2%w/w with 1: 10-10: 1 weight ratio is formed), the microcrystalline Cellulose of 0.5-8%, 0.5-9 the pregelatinized starch of the polyvinylpyrrolidone of weight % and 2-8 weight %, described outer cover layer comprise pH dependent release polymer and one or more pharmaceutically acceptable excipient.
In a preferred embodiment, medicinal tablet of the present invention comprises label and outer cover layer, described label comprises the mesalazine of 60-80 weight %, the hydroxypropyl methylcellulose mixtures of 3-5% (by the hydroxypropyl emthylcellulose (HPMC) that is lower than 200mPas in 2% aqueous solution medium viscosity and the hydroxypropyl emthylcellulose (HPMC) that is higher than 200mPas in the aqueous solution medium viscosity of 2%w/w with 1: 10-10: 1 weight ratio is formed), the microcrystalline Cellulose of 1-5%, 1-7.5 the pregelatinized starch of the polyvinylpyrrolidone of weight % and 2.5-7.5 weight %, described outer cover layer comprise pH dependent release polymer and one or more pharmaceutically acceptable excipient.
A second aspect of the present invention provides a kind of method that obtains the oral drugs tablet of first aspect present invention, and described method comprises following steps:
A) with mesalazine and hydrophilic matrix blending, if had disintegrating agent and binding agent also with its blending, obtaining the mixture of blending, the hydroxypropyl emthylcellulose (HPMC) that described hydrophilic matrix is higher than 200mPas by the HPMC microcrystalline Cellulose (HPMC) that is lower than 200mPas in 2% aqueous solution medium viscosity and viscosity is with 1: 10-10: 1 weight ratio is formed;
B) water, perhaps when in step a), having binding agent with the binder aqueous solution of previous preparation, the mixture pelleting of the blending that step a) is obtained;
C) granule of Huo Deing drying steps b);
D) if there is lubricant, then the granule with drying lubricates and compresses to obtain described label; With
E) comprise the aqueous dispersion of described pH dependent polymers with described pharmaceutically acceptable excipient preparation, and coat described label obtaining outer cover layer, thereby obtain described tablet.
The method that is used for the described tablet of coating can be any conventional method well known by persons skilled in the art.
Advantageously, the aqueous solution of preparation polyvinylpyrrolidone in step b); Drying is carried out in fluidized bed dryer in step c); In step d), add lubricant with the granule of lubricated described drying, compress described blend then to obtain label, the aqueous dispersion of the alcoholic solution of preparation antitack agent and pH dependent polymers and plasticizer obtains outer cover layer to coat described label in step e).
On the other hand, the present invention relates to tablet of the present invention and be used for the treatment of ulcerative colitis.
Provide following examples fully intactly to explain the present invention.
Embodiment
Embodiment 1
Figure BDA00003413721700091
Figure BDA00003413721700101
Mesalazine, HPMC Methocel K4M Premium, HPMC Methocel K100 LV Premium and pregelatinized starch are mixed and use subsequently pure water solution (15%) pelletize of polyvinylpyrrolidone.
Described granule is dry in fluidized bed dryer.Described dried particles is passed suitable mesh screen.These granules are mixed with colloidal silica and microcrystalline Cellulose and lubricated with magnesium stearate.
Compress the final blended thing then.
Coat described tablet with enteric coating suspension (alcoholic solution of Talcum, Eudragit S100, Eudragit L100 and triethyl citrate).
Embodiment 2-3
Use and the similar method of embodiment 1 described method, prepared the tablet that contains HPMC mixture shown in 1000mg mesalazine and the not commensurability table 1.
Figure BDA00003413721700111
* percetage by weight refers to the gross weight of described tablet.
Composed as follows according to embodiment 2 and 3 tablets that produce:
Figure BDA00003413721700112
Figure BDA00003413721700121
Dissolving-out method
For all embodiment, the dissolution of the mesalazine of the described tablet of test in USP Type II device.Dissolution medium (dissolution medium): among the HCl 2 hours, pH6,4 times 1 hour, following 9 hours of pH7.2.
The stripping curve of the preparation of describing among the embodiment 1-3 that obtains is open in Fig. 1.

Claims (21)

1. oral drugs tablet, it is used for control and discharges mesalazine or its officinal salt as active component, and described tablet has label and the outer coating of enteric, it is characterized in that described label comprises:
I) in the gross weight of described tablet, the mesalazine of 40-90 weight %; With
Ii) in the gross weight of described tablet, amount is the hydrophilic matrix of 1-20 weight %, described hydrophilic matrix by the hydroxypropyl emthylcellulose (HPMC) that is lower than 200mPas in 2% aqueous solution medium viscosity and the hydroxypropyl emthylcellulose (HPMC) that is higher than 200mPas in 2% aqueous solution medium viscosity with 10: 1-1: 10 weight ratio is formed;
Described tablet feature is that also the outer coating of described enteric comprises:
Iii) pH dependent release polymer,
In the gross weight of described tablet, the tectal amount of described skin is 5-25%.
2. according to the oral drugs tablet of claim 1, wherein in the gross weight of described tablet, the amount of mesalazine is 50-90 weight %, preferred 60-80 weight %.
3. according to the oral drugs tablet of claim 1, wherein in the gross weight of described tablet, the amount of described hydrophilic matrix is 1-15 weight %, preferred 2-10 weight %, more preferably 3-5 weight %.
4. according to the oral drugs tablet of claim 1, wherein in the gross weight of described tablet, the tectal amount of described skin is 10-20%.
5. according to the oral drugs tablet of claim 1, wherein said hydrophilic matrix is made up of with weight ratio the hydroxypropyl emthylcellulose (HPMC) that is lower than 200mPas in 2% aqueous solution medium viscosity and the hydroxypropyl emthylcellulose (HPMC) that is higher than 200mPas in 2% aqueous solution medium viscosity at 1: 1.
6. according to the oral drugs tablet of claim 1, wherein in the gross weight of described tablet, the amount of described hydrophilic matrix is 1-15 weight %, preferred 2-10 weight %, more preferably 3-5 weight %.
7. according to the oral drugs tablet of claim 1, the amount of wherein said pH dependent release polymer is the outer tectal 15-75 weight % of described tablet.
8. according to the oral drugs tablet of claim 1, wherein said label also comprises the pharmaceutically acceptable excipient that is selected from filler, binding agent, antitack agent, lubricant or disintegrating agent.
9. according to the oral drugs tablet of claim 1, the outer cover layer of wherein said tablet also comprises the pharmaceutically acceptable excipient that is selected from antitack agent, plasticizer or coloring agent.
10. oral drugs tablet according to Claim 8, the amount of wherein said filler is the 0.5-10 weight % of described tablet total weight amount, preferred 0.5-8 weight %, more preferably 1-5 weight %.
11. oral drugs tablet according to Claim 8, the amount of wherein said binding agent are the 0.1-10 weight % of described tablet total weight amount, preferred 0.5-9 weight %, more preferably 1-7.5 weight %.
12. according to Claim 8 with 9 oral drugs tablet, the amount of wherein said antitack agent is the 0.1-5 weight % of described tablet total weight amount, preferred 0.1-3.5 weight %, more preferably 0.1-1.5 weight %, and be up to 30 weight % of described outer cover layer gross weight, be preferably 5-30 weight %.
13. oral drugs tablet according to Claim 8, wherein in the gross weight of described tablet, the amount of described lubricant is 0.1-5 weight %, preferred 0.1-3 weight %.
14. oral drugs tablet according to Claim 8, wherein in the gross weight of described tablet, the amount of described disintegrating agent is 1-10 weight %, preferred 1-8 weight %, more preferably 2.5-7.5 weight %.
15. according to the oral drugs control release tablet of claim 9, wherein in the tectal gross weight of described skin, the amount of described plasticizer is up to 20 weight %, preferred 5-20 weight %.
16. be used for to obtain each the method for oral drugs tablet of claim 1-15, it is characterized in that carrying out following steps:
A) with mesalazine and hydrophilic matrix blending, if had disintegrating agent and binding agent also with its blending, obtaining the mixture of blending, described hydrophilic matrix is by being lower than the HPMC microcrystalline Cellulose (HPMC) of 200mPas and the hydroxypropyl emthylcellulose (HPMC) that is higher than 200mPas in 2% aqueous solution medium viscosity in 2% aqueous solution medium viscosity with 1: 10-10: 1 weight ratio is formed;
B) water, perhaps when in step a), having binding agent with the binder aqueous solution of previous preparation, the mixture pelleting of the blending that step a) is obtained;
C) granule of Huo Deing drying steps b);
D) if there is lubricant, then the granule with drying lubricates and compresses to obtain described label; With
E) comprise the aqueous dispersion of described pH dependent polymers with remaining pharmaceutically acceptable excipient preparation, and coat described label obtaining outer cover layer, thereby obtain described tablet.
17. according to the method for claim 16, wherein in step b), prepare the aqueous solution of polyvinylpyrrolidone.
18. according to the method for claim 16, wherein carry out in fluidized bed dryer dry described in the step c).
19. according to the method for claim 16, wherein in step d), add lubricant with the granule of lubricated described drying, compress described blend then to obtain label.
20. according to the method for claim 16, wherein the aqueous dispersion of the alcoholic solution of preparation antitack agent and pH dependent polymers and plasticizer obtains described outer cover layer then to coat described label in step e).
21. discharging the oral drugs tablet of mesalazine or its officinal salt, each control of claim 1-15 is used for the treatment of ulcerative colitis.
CN2011800629130A 2010-12-27 2011-12-23 Oral pharmaceutical tablet for controled release of mesalazine and process for obtaining it Pending CN103269691A (en)

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ES2463040T3 (en) 2014-05-27

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